Aging on the cellular level involves many paradoxes. On the one hand, many biochemical changes have been documented that suggest a variety of mechanisms of cellular aging. On the other hand, the simple expedient of increasing the expression of the enzyme telomerase is well known to rejuvenate cells and allow them to survive indefinitely and to function normally for an unlimited time [1]. Telomerase is a ribonucleoprotein consisting of 2 subunits, an RNA template component for nucleotide incorporation (TR; referred to as h-TR in humans) and a catalytic protein component (telomerase reverse-transcriptase, or TERT, which is referred to as h-TERT when it is the human version) whose combined primary function is to prevent telomere shortening and to repair and otherwise maintain telomere integrity. Therefore, it is reasonable to conclude that the primary problem of preventing and reversing aging on the level of dividing cells is to maintain healthy telomeres, and that the molecular mechanisms often thought to drive aging on a cellular level are actually either side effects of telomere shortening or drivers of telomere shortening or damage that can be overcome by telomerase induction.
Telomeres are the repetitive segments of DNA found at the ends of all chromosomes. Because of the way DNA is copied by DNA polymerase, the end of a given DNA strand cannot be fully replicated by the polymerase, which leads to a loss of DNA from the end of the replicated DNA strand every time a cell's DNA is copied during the S-phase of the cell division cycle. The failure of DNA polymerase to copy the complete DNA strand is referred to as the “end replication problem” and results in a cumulative shortening of telomeres over many cell divisions. Telomerase can address the end replication problem and thereby maintain telomere lengths constant, but the catalytic subunit (h-TERT in humans) of telomerase is normally not expressed in most somatic (body) cells, which allows the eventual widespread development of aging at the cellular level.
Another key factor besides telomere length is telomere damage, which can produce effects similar to telomere shortening. Telomerase can also repair damaged telomeres, and therefore even levels of telomerase that do not cause telomere lengthening may be therapeutic. This argues in favor of the potential value of even weak telomerase inducers. Weak telomerase inducers might also be safer from the point of view of controlling cancer (see below).
Powerful evidence now suggests that telomere shortening and/or telomere damage can drive aging in non-dividing cells as well. Recent evidence has even linked mitochondrial aging to telomere shortening [2]. Cancer-resistant mice whose telomeres have been elongated live 40% longer than those without telomere elongation [3], and major aging changes induced in mice by telomere shortening, including brain shrinkage and loss of sensory perception, are robustly reversed when telomerase is induced [4]. In humans, life expectancy has been linked to the length of telomeres in blood samples [5]. Therefore, the ability to retain normal healthy telomeres is emerging as a major factor for the control of aging in all somatic cells and in the body as a whole.
Telomerase expression can be induced in cancer cells as the direct or indirect result of genetic damage and can allow the cancer cells to proliferate to a life-threatening extent. This has led to the misconception that expressing telomerase in normal cells will cause them to become cancerous. This is clearly not the case [1, 6], and, in fact, most embryonic and adult stem cells [7] and certain other adult cells needed for the turnover of rapidly dividing cells in selected tissues express active telomerase and remain non-cancerous for life. However, cells that have been artificially induced or engineered to express telomerase (i.e., cells that have been “telomerized”) and that later happen to mutate to a cancerous phenotype may well give rise to cancers that are more difficult to eradicate than usual. For this reason, there is justified widespread caution over the concept of maintaining healthy telomeres as a major approach to the control of aging. Although rapid and “profound” death of cancer cells subjected to telomerase inhibition has been demonstrated [8], and Geron is working toward introducing telomerase inhibitors as anti-cancer agents, it would be desirable to devise a method for maintaining telomeres that minimizes the risk of cancer cell proliferation should cancer arise after telomerization. It would also be desirable to devise a method of telomerization that would allow the induced telomerase expression to be rapidly discontinued should a cancer problem arise, thus potentially simulating the effect of a telomerase inhibitor.
Methods that induce telomerase expression for one cell type should be generally effective for other cell types. The mechanisms responsible for telomerase expression and repression should be universal for all cell types in a given organism, so a method for inducing telomerase one non-postmitotic cell type should be useful as well in other non-postmitotic cells whether they are isolated or reside in tissues, organs, or whole organisms, including humans. In addition, if h-TERT can be successfully induced in human cells by a given intervention, then non-human TERT should generally be successfully induced in non-human cells by the same or by essentially the same intervention. Finally, telomerase induction methods that are effective in living cells are also expected to be effective in and to have valuable uses in the context of cell-free gene expression systems.